Protein synthesis is stimulated by changes of physiological conditions such as those provided by ingestion of foods, exercise, and sleep. Growth hormones secreted from the hypophysis upon receiving these stimuli directly or indirectly act on target organs. When growth hormones indirectly act, insulin-like growth factor 1 (IGF-1) secreted from the liver stimulated by a growth hormone is transported by blood throughout the whole body, and acts on a target organ. It is known that most of human cells, especially cells of muscle, bone, liver, kidney, nerve, skin, and lung, are influenced by IGF-1.
For example, if IGF-1 binds to a target organ, or a receptor of each cell of a tissue, signal transfer starts within the cell. There is the mammalian rapamycin target protein (mTOR) downstream from this signal transfer. The signal transfer system via mTOR works as a sensor for the amino acid balance in the cellular environment of mammals, and participates in the protein synthesis through control of activities of two of the important regulatory factors involved in the translation of proteins, the S6 kinase 1 (S6K1, Non-patent document 1) and the initiation factor 4E-binding protein (4E-BP1, Non-patent document 2) (Patent document 1, Non-patent documents 3 and 4). It is also known that S6K1 and 4E-BP1 activated by being phosphorylated (Non-patent document 5).
Therefore, IGF-1 concentration and activated states of S6K1 and 4E-BP1 (phosphorylated states) are frequently used as indexes of protein synthesis.
In patent documents concerning promotion of protein synthesis, there have been reported a whey protein hydrolysate (Patent document 2), fish ovary membrane (Patent document 3), 11β-hydroxy-4-androstene-3,17-dione (Patent document 4), sterol glycoside derived from germinated brown rice (Patent document 5), and so forth.
Although there are known several substances having a protein synthesis-promoting action as described above, it is not known that extract of Citrus depressa, or a polymethoxyflavonoid such as nobiletin and tangeretin has a protein synthesis-promoting action.
Further, in patent documents concerning the IGF-1 production-promoting action, there have been reported gentiopicrin (Patent document 6), swertiamarin (Patent document 7), Angelica keiskei extract and/or luteolin-7-O-glucoside (Patent document 8), molecular species including Fc region of immunoglobulin G (Patent document 9), sterol glycoside derived from germinated brown rice (Patent document 5), ε-viniferin (Patent document 10), Paeonia albiflora extract (Patent document 11), and so forth.
Although there have been reported several substances having the IGF-1 production-promoting action as described above, it is not known that extract of Citrus depressa, or a polymethoxyflavonoid such as nobiletin and tangeretin show the IGF-1 production-promoting action.
As a plant-derived health food raw material, extract of Citrus depressa attracts attention. Various efficacies of polymethoxyflavonoids such as nobiletin and tangeretin contained in extract of Citrus depressa have been found to date. For example, it is reported that nobiletin has such actions as anti-hypertension and anti-cancer actions (Patent document 12), heart disease preventing and treating actions (Patent document 13), and antiulcer action (Patent document 14). Further, it has been reported that polymethoxyflavonoids such as tangeretin and nobiletin have a neovascularization suppressing action (Patent document 15). Furthermore, it is known that flavonoids contained in Citrus species such as Citrus depressa have a blood pressure elevation suppressing action (Patent document 16).
Furthermore, although there has been reported that nobiletin and tangeretin have a neurite outgrowth action (Patent document 17), it is known that synthesis of new protein is not required for the neurite outgrowth (Non-patent document 6). Further, although possibility of treatment of peripheral nerve functional disorders such as amyotrophic lateral sclerosis with them is also mentioned in Patent document 17, the object of this treatment is limited to improvement of a pathological condition caused by neurite outgrowth, and the patent document suggests neither suppression of muscular atrophy nor synthesis of myoproteins.
As described above, there have been reported various kinds of efficacies of extract of Citrus depressa, or polymethoxyflavonoids such as nobiletin and tangeretin, but it is not known that such extract or substances have an IGF-1 production-promoting action or a protein synthesis-promoting action.
Further, there is also known a muscular fiber type shift inhibitor using a polyphenol contained in fruits of Rosaceae plants such as apple trees, for example, procyanidin, as an active ingredient (Patent document 18). However, the fruit-derived polyphenol as the active ingredient of this muscular fiber type shift inhibitor is limited to those derived from fruits of Rosaceae plants, but polyphenols derived from Rosaceae plants contain polymethoxyflavonoids only at a low content.
Such polymethoxyflavonoids as mentioned above are scarcely contained in fruit juice, but are mostly contained in pericarps. Therefore, only by squeezing fruits, these polymethoxyflavonoids are obtained only at a low content.
Polymethoxyflavonoids constitute one class of flavonoid, have a special structure in which a plurality of phenolic hydroxyl groups are methylated, and are mainly contained in Citrus species. It has also been reported that polymethoxyflavonoids such as nobiletin or tangeretin are metabolized in the liver after ingestion. For example, methoxy groups of nobiletin are converted into hydroxyl groups by metabolism in the liver of rat, and nobiletin derivatives having 4′-OH, 7-OH, 6-OH, 3′,4′-diOH, 6,7-diOH or the like are generated as metabolites. Further, it has been reported that, from tangeretin, tangeretin derivatives having 4′-OH, 3′,4′-diOH, 7,4′-diOH, 6,7-diOH or the like are generated as metabolites (Non-patent document 7).